This new application is enriched by a longitudinal resource that has the potential to provide a better understanding of the neurobiological determinants of alcohol dependence (AD) in offspring from mutliplex alcohol dependence families (high-risk [HR]) and control (low-risk [LR]) families. In families selected for the presence of many cases of AD, there is a greater likelihood that disease genes will be present providing efficient identification of factors influencing intermediate phenotypes for AD risk. We propose a multivariate approach for understanding how brain morphology and functioning in HR offspring impacts their tendency for emotional dysregulation and behavioral disinhibition and the likelihood that they will develop a substance use disorder (SUD). Alterations in brain systems involved in cognition, emotion and altered sensitivity to acquired reinforcers (rewards) are prominent in long term alcoholics. The limbic aspects of this circuitry include the orbitofrontal cortex and amygdala. Changes in this circuitry that are associated with behavioral disinhibition can provide important clues regarding the etiology of AD. A frequent observation in long term AD individuals is that right hemisphere functioning (e.g., visuospatial performance) is more impaired than is the left, with WM deficits seen in right hemisphere tracts connecting prefrontal regions. Building on observations of familial risk group differences in the right orbitofrontal cortex (OFC), especially in white matter (WM) volume, and in the amygdala, this new study will perform diffusion tensor imaging (DTI) in HR and LR offspring to elucidate possible differences in limbic connectivity and relate these to behavioral measures of disinhibition (Aim 1). We plan to investigate gene (G) by environment (E) interactions that may produce structural alterations in key components of brain networks designed for emotional and cognitive regulation and reward (Aim 2). Importantly, the study of the G X E determinants of brain morphology in high risk AD offspring and comparison controls has never been done. Because there is considerable evidence that alcohol has greater neuropathological effects on the developing adolescent/young adult brain, we propose to compare pre-post differences in a sample of HR and LR subjects previously scanned at a time when they had been minimally exposed to alcohol or drugs and who now would be scanned when many have exposure (Aim 3), a unique strategy for measuring exposure effects. Aim 4 will investigate the relationship between right OFC volume and P300 trajectories and SUD outcome. Continued follow-up of these offspring to determine SUD outcome in young adulthood could provide significant clues about the neurobiological underpinnings of multigenerational AD and suggest genes that may be relevant in this neurobiological variation. Importantly, identifying the genetic determinants of brain morphology involved in SUD has the potential for informing intervention, through better identification of those at highest risk, and for suggesting treatment options through genetically informed medication development. PUBLIC HEALTH RELEVANCE: This new application will provide a better understanding of the neurobiological determinants and consequences of alcohol and drug exposure in offspring from families with multiple cases of alcohol dependence (AD). Currently, there is no way to prospectively identify which offspring will survive or succumb to AD or related substance use disorders (SUD). A subsample of the proposed cohort had MRI scans while free of exposure and now would be followed up 6 years later to assess the effects of exposure. Continued clinical follow up is proposed to determine SUD outcome, measure brain regions thought to be involved in SUD in these offspring and controls, relate the brain morphology to selected genes and environmental exposures, thereby providing important clues concerning the neurobiological determinants of multigenerational AD and suggest possible interventions and treatment.